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Perils in the Use of Linkage Disequilibrium for Fine Gene Mapping: Simple Insights from Population Genetics

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Perils in the Use of Linkage Disequilibrium for Fine Gene Mapping: Simple Insights from Population Genetics 3292 Hypothesis/Commentary Perils in the Use of Linkage Disequilibrium for Fine Gene Mapping: Simple Insights from Population Genetics Prakash Gorroochurn Division of Statistical Genetics, Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York Abstract It is generally believed that genome-wide association tary explains why this strategy can be misleading.It (GWA) studies stand a good chance for finding argues that there is an intrinsic problem in the way susceptibility genes for common complex diseases. LD is currently used for fine-mapping.This is Although the results thus far have been somewhat because most of the metrics that are currently used promising, there are still many inherent difficulties to measure LD are inadequate, as they do not take and many initial associations do not get replicated. into account evolutionary variables that shape the LD The common strategy in GWA studies has been that structure of the human genome.Recent research on of selecting the most statistically significant single another metric, based on Male´cot’s model for isola- nucleotide polymorphisms with the hope that these tion by distance, holds considerable promise for will be very physically close to causal variants GWA studies and merits more serious consideration because of strong linkage disequilibrium (LD).Using by geneticists. (Cancer Epidemiol Biomarkers Prev simple ideas from population genetics, this commen- 2008;17(12):3292–7) Introduction Genome-wide association (GWA) studies are well under difficulties inherent in the conventional use of LD. By way and, in their first couple of years, have identified using simple population genetics ideas, this commentary variants for several complex diseases, including at least aims to enumerate specific instances where the results of four types of cancer (1). This seems promising, although LD fine-mapping can be misinterpreted. it remains to be seen how many of these will be Of the several theoretical studies on LD, an important consistently replicated in the future. Once a GWA study simulation-based workis that of Kruglyak(7). Kruglyak is done, there are usually two types of subsequent argued that LD between the common variant and other association studies (2): those aimed at replicating markers was essentially short-ranged and was unlikely the original significant markers (the so-called ‘‘exact’’ to extend beyond a genetic distance of 3 kb. A more approach) and those aimed at fine-mapping other loci recent study (8) found that LD could extend to genetic in the surrounding region in addition to the original distances of 1 Mb. Empirical studies have shown that LD significant loci (the so-called ‘‘local’’ approach). Both the is highly ‘‘patchy’’ in nature and does not decrease original GWA and any follow-up association study monotonically with physical distance. Chromosomes depend crucially on the concept of linkage disequili- tend to contain blocks of long-range LD (which is brium (LD; also known as gametic disequilibrium, allelic different from Kruglyak’s predictions) separated by association, or two-locus Hardy-Weinberg disequili- small region of recombination hotspots (9-11). LD is brium). It is unsurprising therefore that, well before high within blocks but low between blocks. GWA studies were under way, a vital taskwas to elucidate the LD structure of the human genome. This structure could shed considerable light on the prospects Insights from Population Genetics and limitations of LD mapping, especially for GWA. The indiscriminate use of LD can, however, lead to Insight 1: Population History Is a Key Determinant inaccurate results, especially when doing fine-mapping. of LD in Small DNA Regions and There Is Usually No Association studies are usually criticized on design and Correlation between LD and Physical Distance when methodologic grounds (3-6) while underestimating the Doing Fine-Mapping. The cystic fibrosis gene was found by climbing up a gradient until a peakwas reached. However, when the same principles are applied to the Received 8/4/08; revised 8/29/08; accepted 9/15/08. Huntington’s disease (HD) gene, something unexpected Grant support: National Institute of Mental Health grant MH-48858. happens (see Fig. 1). Requests for reprints: Prakash Gorroochurn, Division of Statistical Genetics, The HD gene shows weakLD to some physically close Department of Biostatistics, Mailman School of Public Health, Columbia University, markers (e.g., D4S180) but strong LD to a more Room 620, 722 West 168th Street, New York, NY 10032. Phone: 212-342-1263; Fax: 212-342-0484. E-mail: [email protected] physically distant marker (D4S98). Thus, if both markers Copyright D 2008 American Association for Cancer Research. were tested for association with disease, one (D4S98) doi:10.1158/1055-9965.EPI-08-0717 would show strong association through LD with the HD Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008 Downloaded from cebp.aacrjournals.org on September 28, 2021. © 2008 American Association for Cancer Research. Cancer Epidemiology,Biomarkers & Prevention 3293 gene, whereas the other (D4S180) would show weak large value of Dt (or Dt¶) if mutant alleles at L originated association. This could mislead many to believe that the very recently backin time or if L is located in a HD gene was physically much closer to the D4S98 locus recombination cold spot (14). Another locus could be than to the D4S180 locus when in fact the opposite is true. relatively close to the given locus and result in small Is such erratic LD behavior surprising? Not when values of Dt (or Dt¶). looked from a population genetics perspective. Indeed, Insight 2: Genetic Drift Generates LD between the noncorrelation between LD and physical distance is Disease and Marker Alleles in a Random Fashion, so the norm rather than the exception when dealing with a Particular Disease-Marker Association Found in One small DNA regions (e.g., <100 kb; ref. 12). To understand Population Need Not Exist in Another Population or why, consider the simple equation for LD: Might Even Be in the Opposite Direction. Templeton t (12) provides an example for two linked loci. Both the Dt ¼ D0ð1 À Þ ; ð1Þ human populations living in southern Italy west of the Apennine mountain range and on the nearby island of D t D where t is the LD after generations, 0 is the initial Sardinia were formed from a founder effect. In the Italian u D LD, and is the recombination fraction. ( t is actually population, all Med1 G6PD-deficient males had red/ t the deviation at generation from random association of green color blindness, whereas in the Sardinian popula- u two-locus haplotype frequencies.) When is small (e.g., tion almost none of the Med1 G6PD-deficient males had u À3 D D <10 ), t 0, the value of LD is primarily red/green color blindness. Thus, in both cases, Med1 determined by its initial value (which is a function of G6PD-deficient males are strongly associated with red/ haplotype and allele frequencies) and does not decay green color blindness but in complete opposite direc- with either physical distance or time. Different markers tions. Furthermore, if we had selected cases with red/ at various short distances from a given markers will have green color blindness by sampling from both Italian and D different values of 0 depending on the evolutionary Sardinian populations, it is very likely that no association history of the population. whatsoever would be found. For example, consider three biallelic loci A, B, and C All of this makes sense because populations with small across a small DNA region (e.g., <100 kb), with B closer effective sizes undergo extensive amounts of genetic drift. A a than C to A (see Fig. 2). Suppose A has both and Genetic drift is the random fluctuation of allele frequen- B/B C/C alleles, but B and C have homozygotes and , cies across generations because of finite population size. respectively. We shall consider the normalized LD Let the mutant allele at the G6PD locus be denoted by a D¶ D measure (which equals divided by its theoretical and the allele for color blindness by b, with both alleles maximum value), because it is more indicative of the having relatively small frequencies. Let the wild-type relative strength of LD. Because there is no allelic alleles at each locus be A and B, respectively. Now, for D¶ variation at B and C, = 0 for alleles at A and B and these two loci, we have four haplotypes, with frequencies for alleles at A and C. Suppose now an initial LD is even smaller than those of the corresponding alleles. The created between alleles A and B through gene flow from combination of small effective population size and rare several founders carrying copies of b. At about the same haplotypes means that each one is subject to considerable time in the past, an initial LD is created between alleles A random fluctuation, so that any one of them could and C through a single mutation of a C allele to c. Now, increase in frequency. In our example, the frequency of several copies of b are introduced with some on the same the ab haplotype increased in the Italian population, chromosome as A and others on the same chromosome whereas the frequency of the Ab haplotype increased in as a, whereas the single copy of c will always be the Sardinian population. Therefore, because genetic drift associated with A (or a depending on which chromo- is a stochastic phenomenon, it can create an association some the mutation occurred). Therefore, the initial LD between the alleles at a disease locus and a marker locus D ¶ AC AB 0 will be larger in magnitude for than for , in a completely random fashion.
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